GSTDTAP

浏览/检索结果: 共60条,第1-10条 帮助

限定条件    
已选(0)清除 条数/页:   排序方式:
Nearest neighbours reveal fast and slow components of motor learning 期刊论文
NATURE, 2020, 577 (7791) : 526-+
作者:  Kollmorgen, Sepp;  Hahnloser, Richard H. R.;  Mante, Valerio
收藏  |  浏览/下载:4/0  |  提交时间:2020/07/03

A new method for analysing change in high-dimensional data is based on nearest-neighbour statistics and is applied here to song dynamics during vocal learning in zebra finches, but could potentially be applied to other biological and artificial behaviours.


Changes in behaviour resulting from environmental influences, development and learning(1-5) are commonly quantified on the basis of a few hand-picked features(2-4,6,7) (for example, the average pitch of acoustic vocalizations(3)), assuming discrete classes of behaviours (such as distinct vocal syllables)(2,3,8-10). However, such methods generalize poorly across different behaviours and model systems and may miss important components of change. Here we present a more-general account of behavioural change that is based on nearest-neighbour statistics(11-13), and apply it to song development in a songbird, the zebra finch(3). First, we introduce the concept of '  repertoire dating'  , whereby each rendition of a behaviour (for example, each vocalization) is assigned a repertoire time, reflecting when similar renditions were typical in the behavioural repertoire. Repertoire time isolates the components of vocal variability that are congruent with long-term changes due to vocal learning and development, and stratifies the behavioural repertoire into '  regressions'  , '  anticipations'  and '  typical renditions'  . Second, we obtain a holistic, yet low-dimensional, description of vocal change in terms of a stratified '  behavioural trajectory'  , revealing numerous previously unrecognized components of behavioural change on fast and slow timescales, as well as distinct patterns of overnight consolidation(1,2,4,14,15) across the behavioral repertoire. We find that diurnal changes in regressions undergo only weak consolidation, whereas anticipations and typical renditions consolidate fully. Because of its generality, our nonparametric description of how behaviour evolves relative to itself-rather than to a potentially arbitrary, experimenter-defined goal(2,3,14,16)-appears well suited for comparing learning and change across behaviours and species(17,18), as well as biological and artificial systems(5).


  
A lower X-gate in TASK channels traps inhibitors within the vestibule 期刊论文
NATURE, 2020
作者:  Chen, Tao;  Nomura, Kinya;  Wang, Xiaolin;  Sohrabi, Reza;  Xu, Jin;  Yao, Lingya;  Paasch, Bradley C.;  Ma, Li;  Kremer, James;  Cheng, Yuti;  Zhang, Li;  Wang, Nian;  Wang, Ertao;  Xin, Xiu-Fang;  He, Sheng Yang
收藏  |  浏览/下载:34/0  |  提交时间:2020/07/03

TWIK-related acid-sensitive potassium (TASK) channels-members of the two pore domain potassium (K-2P) channel family-are found in neurons(1), cardiomyocytes(2-4) and vascular smooth muscle cells(5), where they are involved in the regulation of heart rate(6), pulmonary artery tone(5,7), sleep/wake cycles(8) and responses to volatile anaesthetics(8-11). K-2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli(12-15). Unlike other K-2P channels, TASK channels are able to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. As such, these channels are attractive drug targets, and TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnoea and atrial fibrillation(16). In general, potassium channels have an intramembrane vestibule with a selectivity filter situated above and a gate with four parallel helices located below  however, the K-2P channels studied so far all lack a lower gate. Here we present the X-ray crystal structure of TASK-1, and show that it contains a lower gate-which we designate as an '  X-gate'  -created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure is formed by six residues ((VLRFMT248)-V-243) that are essential for responses to volatile anaesthetics(10), neurotransmitters(13) and G-protein-coupled receptors(13). Mutations within the X-gate and the surrounding regions markedly affect both the channel-open probability and the activation of the channel by anaesthetics. Structures of TASK-1 bound to two high-affinity inhibitors show that both compounds bind below the selectivity filter and are trapped in the vestibule by the X-gate, which explains their exceptionally low washout rates. The presence of the X-gate in TASK channels explains many aspects of their physiological and pharmacological behaviour, which will be beneficial for the future development and optimization of TASK modulators for the treatment of heart, lung and sleep disorders.


The X-ray crystal structure of the potassium channel TASK-1 reveals the presence of an X-gate, which traps small-molecule inhibitors in the intramembrane vestibule and explains their low washout rates from the channel.


  
Virtual discovery of melatonin receptor ligands to modulate circadian rhythms 期刊论文
NATURE, 2020, 579 (7800) : 609-+
作者:  Huang, Weijiao;  Masureel, Matthieu;  Qu, Qianhui;  Janetzko, John;  Inoue, Asuka;  Kato, Hideaki E.;  Robertson, Michael J.;  Nguyen, Khanh C.;  Glenn, Jeffrey S.;  Skiniotis, Georgios;  Kobilka, Brian K.
收藏  |  浏览/下载:23/0  |  提交时间:2020/07/03

The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT1 and MT2. Circadian release of melatonin at night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light-dark cycle(1-4). The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep(5,6) and depression(1-4,7-9). Despite their importance, few in vivo active MT1-selective ligands have been reported(2,8,10-12), hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT1 crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT1 inverse agonists-which were topologically unrelated to previously explored chemotypes-that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT1-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT1- but not in MT2-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT1-selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries. A computational screen of an ultra-large virtual library against the structure of the melatonin receptor found nanomolar ligands, and ultimately two selective MT1 inverse agonists that induced phase advancement of the mouse circadian clock when given at subjective dusk.


  
A claustrum in reptiles and its role in slow-wave sleep 期刊论文
NATURE, 2020, 578 (7795) : 413-+
作者:  Loubeyre, Paul;  Occelli, Florent;  Dumas, Paul
收藏  |  浏览/下载:16/0  |  提交时间:2020/07/03

The mammalian claustrum, owing to its widespread connectivity with other forebrain structures, has been hypothesized to mediate functions that range from decision-making to consciousness(1). Here we report that a homologue of the claustrum, identified by single-cell transcriptomics and viral tracing of connectivity, also exists in a reptile-the Australian bearded dragon Pogona vitticeps. In Pogona, the claustrum underlies the generation of sharp waves during slow-wave sleep. The sharp waves, together with superimposed high-frequency ripples(2), propagate to the entire neighbouring pallial dorsal ventricular ridge (DVR). Unilateral or bilateral lesions of the claustrum suppress the production of sharp-wave ripples during slow-wave sleep in a unilateral or bilateral manner, respectively, but do not affect the regular and rapidly alternating sleep rhythm that is characteristic of sleep in this species(3). The claustrum is thus not involved in the generation of the sleep rhythm itself. Tract tracing revealed that the reptilian claustrum projects widely to a variety of forebrain areas, including the cortex, and that it receives converging inputs from, among others, areas of the mid- and hindbrain that are known to be involved in wake-sleep control in mammals(4-6). Periodically modulating the concentration of serotonin in the claustrum, for example, caused a matching modulation of sharp-wave production there and in the neighbouring DVR. Using transcriptomic approaches, we also identified a claustrum in the turtle Trachemys scripta, a distant reptilian relative of lizards. The claustrum is therefore an ancient structure that was probably already present in the brain of the common vertebrate ancestor of reptiles and mammals. It may have an important role in the control of brain states owing to the ascending input it receives from the mid- and hindbrain, its widespread projections to the forebrain and its role in sharp-wave generation during slow-wave sleep.


A structure homologous to the mammalian claustrum exists in reptiles and has a role in generating sharp waves in the brain during slow-wave sleep.


  
Deep sleep drives brain fluid oscillations 期刊论文
SCIENCE, 2019, 366 (6465) : 572-573
作者:  Grubb, Soren;  Lauritzen, Martin
收藏  |  浏览/下载:0/0  |  提交时间:2020/02/17
Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep 期刊论文
SCIENCE, 2019, 366 (6465) : 628-+
作者:  Fultz, Nina E.;  Bonmassar, Giorgio;  Setsompop, Kawin;  Stickgold, Robert A.;  Rosen, Bruce R.;  Polimeni, Jonathan R.;  Lewis, Laura D.
收藏  |  浏览/下载:7/0  |  提交时间:2020/02/17
Spikes in the sleeping brain 期刊论文
SCIENCE, 2019, 366 (6463) : 306-307
作者:  Ikegaya, Yuji;  Matsumoto, Nobuyoshi
收藏  |  浏览/下载:5/0  |  提交时间:2019/11/27
Isolated cortical computations during delta waves support memory consolidation 期刊论文
SCIENCE, 2019, 366 (6463) : 377-+
作者:  Todorova, Ralitsa;  Zugaro, Michael
收藏  |  浏览/下载:1/0  |  提交时间:2019/11/27
Linking the need to sleep with synaptic function 期刊论文
SCIENCE, 2019, 366 (6462) : 189-190
作者:  Cirelli, Chiara;  Tononi, Giulio
收藏  |  浏览/下载:0/0  |  提交时间:2019/11/27
Sleep-wake cycles drive daily dynamics of synaptic phosphorylation 期刊论文
SCIENCE, 2019, 366 (6462) : 201-+
作者:  Bruening, Franziska;  Noya, Sara B.;  Bange, Tanja;  Koutsouli, Stella;  Rudolph, Jan D.;  Tyagarajan, Shiva;  Cox, Juergen;  Mann, Matthias;  Brown, Steven A.;  Robles, Maria S.
收藏  |  浏览/下载:5/0  |  提交时间:2019/11/27